Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I)

Ettaoussi, Mohamed; Sabaouni, Ahmed; Rami, Marouan; Boutin, Jean A.; Delagrange, Philippe; Renard, Pierre; Spedding, Michael; Caignard, Daniel‐Henri; Berthelot, Pascal; Yous, Saı̈d

doi:10.1016/j.ejmech.2012.01.027

Cited by 30 publications

(33 citation statements)

References 36 publications

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“…Another widely used strategy to obtain potent melatoninergic ligands is by replacement of the indole moiety with aromatic fragments. Agomelatine (Figure 1B) is a naphthalene derivative [70,71] that retains a similar binding affinity as melatonin but possesses both melatonin agonist and serotonin antagonist properties ( K i CHO-hMT 1 = 0.1 nM; K i CHO-hMT 2 = 0.12 nM; K i CHO-h5-HT 2C = 708 nM) [72,73]. By mimicking the indane structure of Ramelteon, a dihydrobenzofuran scaffold is linked to the ethylamidomethyl chain by a cyclopropyl ring.…”

Section: Development Of Synthetic Melatoninergicsmentioning

confidence: 99%

A Molecular and Chemical Perspective in Defining Melatonin Receptor Subtype Selectivity

Chan

Wong

2013

IJMS

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Melatonin is primarily synthesized and secreted by the pineal gland during darkness in a normal diurnal cycle. In addition to its intrinsic antioxidant property, the neurohormone has renowned regulatory roles in the control of circadian rhythm and exerts its physiological actions primarily by interacting with the G protein-coupled MT1 and MT2 transmembrane receptors. The two melatonin receptor subtypes display identical ligand binding characteristics and mediate a myriad of signaling pathways, including adenylyl cyclase inhibition, phospholipase C stimulation and the regulation of other effector molecules. Both MT1 and MT2 receptors are widely expressed in the central nervous system as well as many peripheral tissues, but each receptor subtype can be linked to specific functional responses at the target tissue. Given the broad therapeutic implications of melatonin receptors in chronobiology, immunomodulation, endocrine regulation, reproductive functions and cancer development, drug discovery and development programs have been directed at identifying chemical molecules that bind to the two melatonin receptor subtypes. However, all of the melatoninergics in the market act on both subtypes of melatonin receptors without significant selectivity. To facilitate the design and development of novel therapeutic agents, it is necessary to understand the intrinsic differences between MT1 and MT2 that determine ligand binding, functional efficacy, and signaling specificity. This review summarizes our current knowledge in differentiating MT1 and MT2 receptors and their signaling capacities. The use of homology modeling in the mapping of the ligand-binding pocket will be described. Identification of conserved and distinct residues will be tremendously useful in the design of highly selective ligands.

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Section: Development Of Synthetic Melatoninergicsmentioning

confidence: 99%

A Molecular and Chemical Perspective in Defining Melatonin Receptor Subtype Selectivity

Chan

Wong

2013

IJMS

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“…Among the hMT 2 receptor‐selective partial agonists GR 128107, 5‐methoxyluzindole, S 24014, S 24773 (Dubocovich et al, ; Audinot et al, ) and isoamyl agomelatine, the latter shows the highest affinity ( K i = 0.01 nM) and selectivity (7200‐fold) (Ettaoussi et al, ). 4P‐PDOT, an hMT 2 receptor‐selective antagonist with 300‐ to 1500‐fold higher affinity for hMT 2 receptors, is still considered the gold standard for pharmacological characterization of MT receptors (Dubocovich et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…A 140‐fold MT 1 receptor selectivity could be attained by introduction of two fluorine atoms into the N ‐acetyl group of agomelatine. The resulting difluoroagomelatine shows high hMT 1 receptor binding ( K i = 0.03 nM) and is a non‐selective MT 1 –MT 2 receptor full agonist (Ettaoussi et al, ). Very recently, tetrafluoro S26131, the difluoroacetamide analogue of S 26131, has been reported to show higher affinity and selectivity toward hMT 1 receptors than the parent ligand (Zlotos et al , ).…”

Section: Introductionmentioning

confidence: 99%

Update on melatonin receptors: IUPHAR Review 20

Jockers

Delagrange

Dubocovich

et al. 2016

British J Pharmacology

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332

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Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist -MT 1 and MT 2 -encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

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“…This chronotherapeutic agent proved its efficacy in the treatment of major depressive disorders and acts as a melatoninergic MT 1 and MT 2 agonist and a serotoninergic 5‐HT 2C antagonist, probably in a synergic effect of the activities of these three receptors (McAllister‐Williams et al ., ). Agomelatine presents high affinity for both MT 1 and MT 2 receptors (MT 1 : p K i = 9.92; MT 2 : p K i = 9.24) and a lower affinity against 5‐HT 2C (p K i = 6.2) (Ettaoussi et al ., ). Thus, we aim to develop new melatoninergic ligands with an improved pharmacological profile with regard to agomelatine.…”

Section: Introductionmentioning

confidence: 98%

Enantioseparation and thermodynamic study of naphthalene derivatives, new melatoninergic agonists, on coated amylose [tris(S)‐1‐phenylethylcarbamate] stationary phase. Transposition to preparative scale

Landagaray

Yous

Vaccher

et al. 2014

Biomedical Chromatography

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This work reports a high-performance liquid chromatography normal-phase methodology to elucidate enantiomers of naphthalene derivatives, evaluated as melatoninergic agonists. For this purpose four different polysaccharide based chiral stationary phases were evaluated, namely Chiralcel OD-H (cellulose tris-3,5-dimethylphenylcarbamate), Chiralcel OJ (cellulose tris-methylbenzoate), Chiralpak AD (amylose tris-3,5-dimethylphenylcarbamate) and Chiralpak AS (amylose tris-(S)-1-phenylethylcarbamate) with different alcoholic modifiers on different amounts in n-heptane. A temperature study was carried out, between 20 and 40 °C and the apparent thermodynamic parameters were calculated thanks to the Van't Hoff linearization. For all compounds (except 3), ΔΔH° and ΔΔS° exhibited positive values ranging from 791.2 to 9999.3 J/mol and from 3.9 to 37.8 J/K/mol respectively, indicating entropically driven separations. Optimized conditions led to goof resolution of 2.37 for compound 1 on Chiralpak AS, with heptane-2-propanol 90:10 (v/v), at a temperature of 30 °C. Then they were transposed to the preparative scale for compound 1, generating 22 mg of each enantiomer with an 80% yield. The limits of detection and of quantification were determined to allow the calculation of the enantiomeric excess. They were found with very low values, equal to 0.32 and 1.05 µ m and 0.33 and 1.11 µ m, respectively, for peaks 1 and 2 of compound 1.

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Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I)

Cited by 30 publications

References 36 publications

A Molecular and Chemical Perspective in Defining Melatonin Receptor Subtype Selectivity

A Molecular and Chemical Perspective in Defining Melatonin Receptor Subtype Selectivity

Update on melatonin receptors: IUPHAR Review 20

Enantioseparation and thermodynamic study of naphthalene derivatives, new melatoninergic agonists, on coated amylose [tris(S)‐1‐phenylethylcarbamate] stationary phase. Transposition to preparative scale

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